Respiratory syncytial virus (RSV) infection can cause severe bronchiolitis and pneumonia in infants and is the primary cause of hospitalization in newborns and infants. However, RSV is generally well-controlled in otherwise healthy adults. Airway epithelial cells (AECs) constitute the primary target of RSV infection. Epithelial cells pla an important role in antiviral host defense by secreting type I (IFN ?/) interferons that in tur promote expression of interferon-stimulated genes (ISGs). ISGs play a critical role in inhibiting viral replication. IFN-stimulation also causes the production of chemokines such as CXCL10 from epithelial cells that recruit leukocytes to eliminate the virus. We and others have shown that specific growth factors and cytokines such as KGF and IL-22 have epithelial-protective functions. An important source of these factors is the ?? T cell. IL-22 produced by ?? T cells affords mucosal barrier function for lung and intestinal epithelial cells. It is believed that the primary function of ?? T cells is neonatal protection. Previously published human data and our own mouse data show severe loss of IL-22+?? T cells upon RSV infection in early life. Thus, inadequacy of epithelial and ?? T cell function in early life can be expected to cause more severe disease during RSV infection. In preliminary studies, RSV infection of human AECs induced several genes with the highest level of response observed for multiple ISGs, including OASL, as determined by RNA-seq analysis. OASL was recently shown to inhibit RSV replication in epithelial cell lines. Expression of infection-induced mucin gene was inhibited by IL- 22 while decrease in expression of a ZO-1-like tight junction protein was prevented. Upon incubation with rIL- 22 a striking inhibition of viral replication was observed in the human AECs. In mouse studies, RSV infection resulted in a drastic loss of IL-22-producing ?? T cells, especially in infant mice. RSV induced a weaker CXCL10 response from AECs of infant mice as compared to that from older mice. Collectively, these observations prompt us to hypothesize that the susceptibility to RSV-induced disease in early life is due to inadequate epithelial cell and innate immune antiviral defense response that impair effective host defense against RSV. To prove our hypothesis, we will: Aim 1. Investigate the role of ?? T cells and its mediator IL-22 in protectin from RSV infection. Aim 2. Characterize anti-viral defense mechanisms that are induced in RSV-infected human airway epithelial cells and in vivo in mice in the presence or absence of IL-22. Aim 3. Determine the mechanism by which RSV infection results in reduced numbers of ?? T cells and IL-22 production by these cells in infant mice. After completion of the proposed studies, we expect to gain a better understanding of interactions between the innate immune system and airway epithelial cells that protect the host from RSV infection.